ASH 2025 | Genome editing for treatment of JAK2 V617F-driven myeloproliferative neoplasms

Our study is really motivated by the observation that JAK2 inhibitors, while they provide some tremendous clinical benefit, they really fail to actually eliminate the mutant cells. So in most patients, we don’t see a reduction in variant allele frequency. But we know that those patients that do have a reduction in variant allele frequency are those that go on to have much better long-term outcomes. So we were wondering, and actually other groups before us were wondering how we could achieve a more potent reduction in variant allele frequency. And this is where genome editing may come in, which essentially allows us to, on a genetic level, target the V617F mutation and inactivate those alleles. So we found this allele-selective targeting strategy, which essentially means that the CRISPR system will only inactivate the V617F mutant copies, but not the wild-type copies of JAK2. And we have found this to be really effective in primary patient cells to selectively inactivate the mutant alleles. And across a variety of assays and model systems, we show that after eliminating the mutant copies of the gene, we can really sort of normalize the gene expression profile of these cells, and we see evidence of a return to a more normal phenotype of these cells. We also undertook some animal studies with xenografted cell lines that show that we can fundamentally revert a whole set of MPN hallmarks, so we believe there’s a potential therapeutic angle to targeting V617F on a genetic level using genome editing.

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